Thiomorpholine-coumarin derivatives

ABSTRACT

THE PRESENT INVENTION RELATES TO NEW COUMARIN COMPOUNDS USEFUL AS CORONARY DILATORS AND HAVING THE FORMULA   2-(O=),3-((R3)M-C6H4-COO-CH(-CH2-R)-CH2-),4-R1,(R2)2-2H-   CHROMENE   OR THE HYDROCHLORIC ACID ADDITION SALTS THEREOF, AND TO METHODS OF PREPARING THE SAME EITHER BY ACYLATING, IN THE PRESENCE OF ACID-BINDING AGENTS, IF DESIRED, COUMARIN DERIVATIVES HAVING THE FORMULA   2-(O=),3-(R&#39;&#39;-CH2-CH(-OH)-CH2-),4-R1,(R2)2-2H-CHROMENE   WITH ACYLATING AGENTS SELECTED FROM THE GROUP CONSISTING OF ALKOXYBENZOIC ACID HAVING THE FORMULA   ((R3)M-PHENYL)-COOH   AND FUNCTIONAL DERIVATIVES THEREOF, OR BY CONDENSING, IN THE PRESENCE OF ACID-BINDING AGENTS, IF DESIRED, COUMARIN DERIVATIVES HAVING THE FORMULA   2-(O=),3-((R3)M-C6H4-COO-CH(-CH2-R4)-CH2-),4-R1,(R2)2-   2H-CHROMENE   WITH AN AMINE HAVING THE FORMULA RH, WHEREIN R IS THIOMORPHOLINO, WHICH IS BOUND VIA ITS NITROGEN ATOM; R1 IS SELECTED FROM THE GROUP CONSISTING OF ALKYL RADICALS HAVING 1-4 CARBON ATOMS AND PHENYL; R2 IS SELECTED FROM THE GROUP CONSISTING OF 5,7-,6,7-AND 7,8-POSITIONED ALKOXY GROUPS HAVING 1-4 CARBON ATOMS; R2 IS SELECTED FROM ALKOXY GROUPS HAVING 1-4 CARBON ATOMS; R4 IS SELECTED FROM THE GROUP CONSISTING OF CHLORINE AND BROMINE; R&#39;&#39; IS THIOMORPHOLINO, WHICH IS BOUND VIA ITS NITROGEN ATOM; AND M IS SELECTED FROM THE GROUP CONSISTING OF 1,2, AND 3.

United States Patent Office 3 Claims ABSTRACT OF THE DISCLOSURE The present invention relates to new coumarin compounds useful as coronary dilators and having the formula with acylating agents selected from the group consisting of alkoxybenzoic acid having the formula (Rah:

and functional derivatives thereof, or by condensing, in the presence of acid-binding agents, if desired, coumarin derivatives having the formula with an amine having the formula RH, wherein R is thiomorpholino, which is bound via its nitrogen atom; R is selected from the group consisting of alkyl radicals hav- 3,772,280 Patented Nov. 13, 1973 ing 1-4'carbon atoms and phenyl; R is selected from the group consisting of 5,7-, 6,7- and 7,8-positioned alkoxy groups having 1-4 carbon atoms; R is selected from alkoxy groups having 1-4 carbon atoms; R, is selected from the group consisting of chlorine and bromine; R is thiomorpholino, which is bound via its nitrogen atom; and m is selected from the group consisting of 1, 2, and 3.

The present application is a division of our U.S. Ser. No. 789,919, filed Jan. 8, 1969, now U.S. Pat. No. 3,652,- 557, issued Mar. 28, 1972.

The present application relates to new pharmacologically valuable, basically substituted coumarin compounds having the formula ah (D or the hydrochloric acid addition salts thereof, wherein R is thiomorpholino which is bound via its nitrogen atom; R is selected from the group consisting of alkyl radicals having 1-4 carbon atoms; R is selected from the group consisting of 5,7-, 6,7-, and 7,8-positioned alkoxy groups having 1-4 carbon atoms; R is selected from alkoxy groups having l-4 carbon atoms; and m is selected from the group consisting of 1, 2, and 3.

The coumarin compounds according to the present invention are obtained in the different known per se methods, the method chosen depending on the envisaged constitution of the final product.

The simplest method of obtaining the coumarin compounds according to the present invention is to acylate, optionally in the presence of an acid-binding agent, a conmarin derivative having the formula om-on-om-n' wherein R is thiomorpholino which is bound via its nitrogen atom, with an alkoxybenzoic acid having the formula HO O O (III) Another method of preparing the compounds of the 3 4 present invention which have the General Formula I cona platin electrode of the Gleichmann-Liibbers type (see sists in that coumarin derivatives of the general formula U. Gleichmann and D. W. Liibbers Die Messung des R1 Sauerstoffdruckes in Gasen and Fliissigkeiten mit der 1 Platin-Elektrode unter besonderer Beriicksichtigung der Messung im Blut, Pfliigers Arch. 271, 431-455 (1960) The heart rate was continuously measured by electronic I methods from systolic peaks of the arterial blood pres- \O/ sure. The arterial blood pressure was measured in the known manner in the femoral-artery with the aid of an electromanometer of the Statham-strain-gauge type.

The following table gives the results of the pharmacological investigations which were carried through. The (R3)!n (1V) preparation was tested in the form of its dihydrochloride:

Maximal increase in oxygen Maximal change in the Maximal change in the tension in the coronary heart rate blood pressure (systolic/ LD5U, Dosage, veinous blood diastolic) El e, s-Ike, Preparation mouse 1.v. In percent In minutes In percent In minutes In percent In rmnutes 3-[y-thiomorpholino-fl-(3,4,5-trimethoxybenzwherein Hal stands for a halogen atom are reacted, op- In the preparation of drages and tablets containing as tionally in the presence of an acid-binding agent, with an essential active ingredient the coumarin derivatives of amine of the general formula RH. our invention these substances may be admixed with the Particularly used as amines or bases having the general conventional solid tabletting adjuvants, such as starch, formula RH are all compounds mentioned above in conlactose, talc and the like. Any of the tabletting materials nection with the definition of the radical R. and carriers customary in pharmaceutical practice may The starting materials of the general Formula IV are be employed. obtained by acylating the corresponding S-y-halogen-B- For the preparation of the injection solutions the hydrohydroxy-propyl-coumarins with an alkoxybenzoic acid chlorides of the coumarin derivatives are particularly of the general formula suited since they have mostly a good water-solubility. Injection solutions of water-insoluble products may of course be prepared in the conventional manner by con- 40 currently using well known suspending agents, emulsi- (Rom fiers and/ or solubilizers.

For a better understanding of the nature and the ob- (V) jects of this invention, reference should be made to the accompanying example which is of an illustrative rather than a limiting nature. Unless otherwise stated, all temperatures given are in degrees centigrade.

or with a functional derivative thereof. The reaction may EX MPLE be performed in the presence or absence of an inert sol- 379 g (0.1 mol) 3 thiomorpholino I3 hydroxy vent and possibly in the presence of an acid-binding agent.

propyl] 4 methyl-7,8-d1methoxy-coumar1n are suspended, As low-molecular alkyl rad1cals R and alkoxy radicals with the addition of 121 g. (Q12 mol) triethylamine in 2 of 3 are used partlculafly those having carbon 240 cc. anhydrous toluene. Subsequently, a solution conatomssisting of 27.6 g. (0.12 mol) 3,4,5-trimethoxybenzoylchloderivatives Ohtalnahle under f Present ride in 130 cc. anhydrous toluene is added while stirring invention are valuable pharmaceutics. In partlcular, they at room temperature and the reaction mixture i h d eXcelleht Corollary dilators in this p to 80. Stirring is continued for 12 hours at this tempera- Perlor other known Substances having Such P P ture. The toluene solution is sucked off, while hot, from Their salts are colorless, crystalline substances that easily th separated triethylamine hydrochloride and the filtrate dlssolve in water. is evaporated to dryness in vacuo. The residue is dis- With respect to the Change in the Oxygen teIlSiOIl in the solved in methylene chloride. The methylene chloride coronary veinous blood, the pharmacological investigation solution is washed with dilute aqueous sodium hydroxide of the vasodilator action on the coronary vessels was carolution and subsequently with water and then freed from ried out in dogs according to the methods described by the solvent in vacuo. The residue is recrystallized from W. K. A. Schaper and his co-workers (see W. K. ethyl acetate. In order to precipitate the hydrochloride, Schrflper, XhOImellX, and Bogaard Ube (1 the base thusly obtained is dissolved, with gentle heatkontinuierliche Messung des Sauerstotrdruckes in vendsen ing, in ethyl acetate and then admixed with etheric hydro- Coronarblut (Naunyn-Schmiedebergs Arch. exp. Path. chloric acid until congo paper turns blue. Obtained is the u. Pharmak. 245, 383-389 (1963) The test preparations 3-[v-thiomorpholino-fi-3,4,5-trimethoxybenzoxy propyl] were applied intravenously to the narcotized and spon- 4-methyl-7,8-dimethoxy-coumarin hydrochloride in the taneously breathing animals. On these test conditions the form of colorless needles melting at 208-2l1. Yield: dilatation of the coronary arteries caused by the test sub- 48 g.=7 8.8% of the theoretical.

stances along with the increase in the coronary blood The 3 ['y thiomorpholino p hydroxy-propyll-4- flow led to an increase in the oxygen tension in the methyl-7,8-dimethoxy-coumarin required as starting matecoronary velnous blood. This oxygen tension was measrial may be prepared according to the following process:

ured according to polarographic methods by means of 31.3 g. (0.1 mol) 3-('y-chloro-B-hydroxy-propyl)-4-meth- 5 yl-7,S-dimethoxy-coumarin, prepared according to the method described in British Pat. 1,135,907, Example 2, para 2, and 30.9 g. (0.3 mol) thiomorpholine are dissolved in 300 cc. chlorobenzene and, after the addition of 12.7- g. (0.12 mol) sodium carbonate, heated while stirring to 120. Stirring is continued for 12 hours at this temperature and then the reaction mixture is sucked off, while hot, from the inorganic salts. The filtrate is evapo rated to dryness in vacuo and, for further purification, the residue thusly obtained is recrystallized from ethyl acetate. Obtained is the 3-[v-thiomorpholino-B-hydroxypropyl]-4-methyl-7,S-dirnethoxy-coumarin in the form of colorless crystals melting at 157. Yield: 27 g.=86.3% of the theoretical.

What is claimed is: 1. A coumarin compound having the structural for- (Ram or the hydrochloric acid addition salts thereof, wherein R is selected from the group consisting of alkyl radicals having 1-4 carbon atoms;

R is selected from the group consisting of 5,7-, 6,7-, and 7,8-positioned alkoxy groups having 1-4 carbon atoms; and

R is selected from alko-xy groups having 1-4 carbon atoms; and

m is selected from the group consisting of 1, 2, and 3.

2. Coumarin compound according to claim 1, wherein R is methyl; R is methoxy; R is methoxy; and m is 3.

3. 3-[7-thi0m01ph0lin0 B (3,4,5-trimethoxybenzoxy) r propyl]-methyl-7,8-dimethoxy-coumarin.

References Cited 20 UNITED STATES PATENTS 3,467,675 9/1969 Petersen et a1. 260243 B 3,534,085 10/1970 Narayanan et al. 260-243 B RICHARD J. GALLAGHER, Primary Examiner 

